Shiga Toxin (STx)-producing bacteria of the Shigella genus and enterohemorrhagic E. coli (EHEC) species infect over 150 million individuals each year and cause over a million deaths. See Ochoa and Clear, Oski's peadiatrics: principles and practice. F. R. McMillan J A, DeAngelis C, Jones M D, Ed., (Lippincott Williams and Wilkins, Philadelphia, 2006). There is no definitive medical treatment. Indeed, treatment with antibiotics is contraindicated because it increases the risk of STx release and life threatening disease. See Mohawk, et al., Microb Pathog 48, 131 (2010); and Wong, et al., N Engl J Med 342, 1930 (2000).
STx consists of a monomeric A-subunit bound to a homopentameric B subunit. The A-subunit contains the enzymatic activity of the toxin that blocks protein synthesis by inhibiting the 28S RNA of the 60S ribosomal subunit while the B-subunit mediates subcellular trafficking of the toxin. The trafficking itinerary of STx involves association of the B-subunit with its cell surface receptor followed by trafficking to early and recycling endosomes (EE and RE), transit to the Golgi from the EE/RE via the bypass pathway, which bypasses more acidic late endosomes (LE), delivery to the endoplasmic reticulum (ER) and eventual extraction to the cytoplasm (FIG. 1). See, for example, Fraser, et al., Nat Struct Biol 1, 59 (1994); Johaness and Popoff, Cell 135: 1175-1187 (2008); Sandvig and van Deurs, EMBO J. 19: 5943-5950 (1994); and Mallard, et al., J Cell Biol 143: 973-990 (1998). Direct transit of STx from the EE/RE to the Golgi via the bypass pathway allows STx to avoid degradation by avoiding exposure to the degradative action of lysosomal hydrolases that are active in the acidic LE compartment. GPP130, a singe pass transmembrane protein that constitutively cycles between the Golgi and endosomes, is required for the endosome-to-Golgi trafficking of STx (FIG. 1). Linstedt, et al., Mol Biol Cell 8: 1073-1087 (1997); Bachert, et al., Mol Biol Cell 12: 3152, (2001); and Puri, et al., Traffic 3: 641-653 (2002). A need exists for specific inhibitors of GPP130 that can be used to block STx trafficking.